The overall goal of this research program is to define the signal transduction mechanisms that mediate the response of cells to inflammatory cytokines and environmental stress. A focus of the study is the c-Jun NH2-terminal kinase (JNK) group of MAP kinases, which are activated in response to cytokines and stress. Many of the components of the JNK protein kinase signal transduction pathway have been identified by molecular cloning and have been characterized in biochemical studies. However, an understanding of the functional significance of the JNK signaling pathway in vivo has remained elusive. Recently, the PI has constructed mice with germ-line mutations in the three gene that encode the JNK protein kinases (Jnk1, Jnk2 and Jnk3) and in both of the genes that encode the protein kinases that phosphorylate and activate JNK (Mkk4 and Mkk7). Comparison of cells with wild-type and mutant genotypes can therefore provide important information concerning the physiological function of the JNK signaling pathway. A specific focus of this proposal is to define the functional significance of the JNK signal transduction pathway. Achievement of the goals of this proposal will increase understanding of the MAP kinase signal transduction in vivo. The information represents a basis for the design of novel therapeutic strategies for the treatment of [1] inflammation, and [2] proliferative diseases such as psoriasis and cancer. The specific aims of this proposal are to examine the effects of the JNK signaling pathway on : 1. Apoptosis and cell survival; 2. Oncogenic transformation and 3. Gene expression.